This proposal aims to delineate the molecular mechanisms and signaling pathways underlying epithelial renewal and carcinogenesis in the bladder using a well-characterized mouse model of urinary tract infections (UTIs). In this model, the host defense response to infection with uropathogenic E. coli (UPEC) results in a rapid but controlled activation of the urothelial renewal process. Key molecular regulators of normal urothelial renewal include the Bmp4 and Shh signaling pathways, which may also be mutated or abrogated during development of bladder carcinoma. Loss of function analyses of these pathways will be performed to determine their role in bladder carcinogenesis. In addition, the urothelial responses to UPEC infection and BCG immunotherapy (a major treatment for bladder carcinoma) will be compared and contrasted in wild type, and Shh- or Bmp4-signaling deficient mouse bladders. Understanding the role of these pathways in bladder carcinogenesis may lead to development of therapeutic modalities for bladder carcinoma treatment using UPEC as a targeted delivery system. Finally, in vitro urothelial explant models will be developed to test pharmacological modulation of the Shh- or Bmp4-signaling pathways. [unreadable] [unreadable] [unreadable]